title: Small molecule enoxacin is a cancer-specific growth inhibitor that acts by enhancing TAR RNA-binding protein 2-mediated microRNA processing.
abstract: MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression at the posttranscriptional level and are critical for many cellular pathways. The disruption of miRNAs and their processing machineries also contributes to the development of human tumors. A common scenario for miRNA expression in carcinogenesis is emerging that shows that impaired miRNA production and/or down-regulation of these transcripts occurs in many neoplasms. Several of these lost miRNAs have tumor-suppressor features, so strategies to restore their expression globally in malignancies would be a welcome addition to the current therapeutic arsenal against cancer. Herein, we show that the small molecule enoxacin, a fluoroquinolone used as an antibacterial compound, enhances the production of miRNAs with tumor suppressor functions by binding to the miRNA biosynthesis protein TAR RNA-binding protein 2 (TRBP). The use of enoxacin in human cell cultures and xenografted, orthotopic, and metastatic mouse models reveals a TRBP-dependent and cancer-specific growth-inhibitory effect of the drug. These results highlight the key role of disrupted miRNA expression patterns in tumorigenesis, and suggest a unique strategy for restoring the distorted microRNAome of cancer cells to a more physiological setting.
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, 08908 L'Hospitalet, Barcelona, Catalonia, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Melo
authors.forename: Alberto
authors.initials: A
authors.lastname: Villanueva
authors.forename: Catia
authors.initials: C
authors.lastname: Moutinho
authors.forename: Veronica
authors.initials: V
authors.lastname: Davalos
authors.forename: Riccardo
authors.initials: R
authors.lastname: Spizzo
authors.forename: Cristina
authors.initials: C
authors.lastname: Ivan
authors.forename: Simona
authors.initials: S
authors.lastname: Rossi
authors.forename: Fernando
authors.initials: F
authors.lastname: Setien
authors.forename: Oriol
authors.initials: O
authors.lastname: Casanovas
authors.forename: Laia
authors.initials: L
authors.lastname: Simo-Riudalbas
authors.forename: Javier
authors.initials: J
authors.lastname: Carmona
authors.forename: Jordi
authors.initials: J
authors.lastname: Carrere
authors.forename: August
authors.initials: A
authors.lastname: Vidal
authors.forename: Alvaro
authors.initials: A
authors.lastname: Aytes
authors.forename: Sara
authors.initials: S
authors.lastname: Puertas
authors.forename: Santiago
authors.initials: S
authors.lastname: Ropero
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: George A
authors.initials: GA
authors.lastname: Calin
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015365:Enoxacin / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000099253:Trans-Activation Responsive RNA-Binding Protein
chemical_list: D000970:Antineoplastic Agents; D015365:Enoxacin; D035683:MicroRNAs; D016601:RNA-Binding Proteins; D054852:Small Molecule Libraries; D000099253:Trans-Activation Responsive RNA-Binding Protein